The idea that the tumor environment is intrinsically immunogenic and, therefore, contains cells capable of mounting an immune response and inducing tumor regression has served as the basis for many immunotherapeutic clinical trials. (Treves, A. J. et al., J. Natl. Cancer Inst. 54:777-780 (1975); Lee, et al., J. Exp. Med. 147:912-922 (1978); Zarling, et al., Nature (London), 280:685-687 (1979); Vose, et al., Nature (London), 296:359-361 (1982); Vose, et al., Int. J. Cancer, 29:33-39 (1982); Vanky, et al., J. Exp. Med., 155:83-95 (1982); Mitsuya, et al., J. Exp. Med., 158:994-999 (1983); De Vries, et al., J. Immunol., 132:510-519 (1984); Slovin, S. F. et al., J. Immunol., 137:3042-3048 (1986); Itoh, K. et al., Cancer Res. 46:3011-3017 (1986); Rosenberg, et al., Science 233:1318-1321 (1986); Rabinowich, et al., Cancer Res. 47: 173-177 (1987); Miescher, et al., J. Immunol. 138:4004-4011 (1987); Kradin, et al., Cancer Immunol. Immunother. 24:76-85 (1987)). In particular, this approach has led to the use of tumor-infiltrating lymphocytes (TILs) in clinical trials (Id.). In this procedure lymphocytes, isolated from tumors, are grown ex vivo in the presence of the lymphokine interleukin-2 (IL-2). The patients are then reinfused with their TILs after the latter have been expanded in culture for several weeks.
Although adoptive immunotherapy using TILs appears highly efficacious (in the largest study to date, regression of tumors was observed in 40% to 60% of metastatic melanoma patients (Rosenberg, et al., New Engl. J. Med. 319:1676-1680 (1988))), the particular characteristics of the tumor environment that produce TILs in vivo remain unclear. Two classes of stimuli, one derived from cell-cell contact between tumor cells and immunocytes and the other from soluble factors may influence activation, homing and proliferation of lymphoid and/or myeloid cells (two basic host defense systems) in vivo.
While interleukin-2 is a soluble factor that acts as a potent mitogen for T-cells (members of the first host defense system) and may induce proliferation of T-cells that specifically home to the tumor, its biosynthesis appears to be confined to immunocytes (Smith, K. A. Science, 240:1169-1176 (1988)) and its presence is not characteristic of the tumor environment. Interleukin-2 is generally non-selective in activating T-cells as all lymphocytes have IL-2 receptors. Thus, while IL-2 is a potent mitogen, it does not specifically select and induce proliferation of the TIL phenotype.
The second important host defense system against tumor growth is the myeloid mononuclear phagocyte system. Mononuclear phagocytes need to be differentiated into mature macrophages and activated to acquire cytotoxic activity before they may be successfully used in the treatment of tumors (Bartholeyns, et al., Anticancer Res. 11:1201-1204 (1991)). This differentiation and activation may occur through modulation by endogenous signals in the tumor environment inducing them to secrete growth factors.
It is thus desirable to specifically recruit lymphocytes to mount an immune response against a targeted tumor. This may be accomplished by providing factors that specifically act to select and proliferate tumor infiltrating lymphocytes or by providing factors that specifically act to induce differentiation and activation of mononuclear macrophages. It is most likely that such factors may be derived from the tumor environment. However no such factors have been previously identified.